The present invention relates to 1-phenyl-3-dimethylaminopropane compounds, to a method of preparing them, and to the use of these substances as pharmaceutical active ingredients.
The treatment of chronic and non-chronic pain situations is of great importance in medicine. This is reflected in the large number of publications. Thus, for example, 1-naphthyl-3-aminopropane-1-ols with an analgesic-narcotic effect are known from EP 176 049. Secondary and tertiary alcohols with xcex3-amino groups are described in J. Pharm. Sci. 59, 1038 (1970) and in J. Prakt. Chem. 323, 793 (1981); phenyl-dimethylaminopropanols containing a para-substituted phenyl radical are described in Chem. Abstr. 54, 20936c (1960) and in Chem. Abstr. 63, 6912e (1965). These compounds also possess analgesic properties. In contrast, the 3-dimethylaminopropan-1-ols containing 2-phenyl radicals described in DE 32 42 922 have an antidepressant effect. The 1-phenyl-propan-1-ols described in J. Pharm. Sci. 57, 1487 (1968) have different pharmacological effects depending on the xcex3-aza ring.
Opioids have been used for many years as analgesics for the treatment of pain, although they give rise to a series of side effects, for example addiction and dependency, respiratory depression, gastrointestinal inhibition and obstipation. They can therefore only be given over an extended period of time or in higher doses subject to special precautionary measures such as special prescription regulations (Goodman, Gilman in xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, Pergamon Press, New York (1990)).
Tramadol hydrochloridexe2x80x94(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloridexe2x80x94assumes a special position amongst centrally-acting analgesics, since this active ingredient gives rise to a pronounced inhibition of pain without the side effects which are known for opioids (J. Pharmacol. Exptl. Ther.4 267, 331 (1993)). Tramadol is a racemate and consists of identical amounts of (+) and (xe2x88x92) enantiomer. In vivo the active ingredient forms the metabolite O-desmethyl-tramadol, which is likewise present as a mixture of enantiomers. Investigations have shown that both the enantiomers of tramadol and the enantiomers of tramadol metabolites contribute to the analgesic effect (J. Pharmacol. Exp. Ther. 260, 275 (1992)).
The underlying object of the present invention was to provide substances with an analgesic effect, which are suitable for the treatment of severe pain without giving rise to the side effects which are typical of opioids.
A further object was to provide analgesic substances which do not exhibit the side effects, for example nausea and vomiting, which occur during treatment with tramadol in some cases.
It has been found that these stringent requirements are fulfilled by certain 1-phenyl-3-dimethylaminopropane compounds. These substances are characterized by a pronounced analgesic effect which is significantly enhanced compared with that of tramadol.
The present invention accordingly relates to 1-phenyl-3-dimethylaminopropane compounds of formula I 
in which
X represents OH, F, Cl, H or an OCOR6 group in which R6 is a C1-3-alkyl group;
R1 is a C1-4-alkyl group;
R2 represents H or a C1-4-alkyl group and R3 represents H or a straight chain C1-4-alkyl group, or R2 and R3 together constitute a C4-7 cycloalkyl radical, and
if R5 is H, R4 represents meta-Oxe2x80x94Z, where Z is H, C1-4-alkyl, PO(OC1-4-alkyl)2, CO(OC1-5-alkyl), CONHxe2x80x94C6H4xe2x80x94(C1-3-alkyl) or COxe2x80x94C6H4xe2x80x94R7, wherein R7 is ortho-OCOC1-3-alkyl or meta- or para-CH2N(R8)2, where R8 is C1-4-alkyl or 4-morpholino, or R4 represents meta-Sxe2x80x94C1-3-alkyl, meta-Cl, meta-F or meta-CR9R10R11, ortho-OH, ortho-Oxe2x80x94C2-3-3-alkyl, para-F or para-CR9R10R11, where R9, R10 and R11 represent H or F, or
if R5 represents Cl, F, OH or Oxe2x80x94C1-3-alkyl in the para-position, R4 represents Cl, F, OH or Oxe2x80x94C1-3-alkyl in the meta-position, or
R4 and R5 together represent 3,4-OCHxe2x95x90CH2xe2x80x94 or 3,4-OCHxe2x95x90CHOxe2x80x94, as diastereoisomers or enantiomers in the form of free bases or salts of physiologically acceptable acids.
1-phenyl-3-dimethylaminopropane compounds of formula I are preferred in which X constitutes OH, F, Cl or H; R1 represents a C1-4-alkyl group; R2 represents H or CH3, and R3 represents H or CH3, and if R5 is H, R4 represents OC1-3-alkyl, xe2x80x94OH, xe2x80x94Sxe2x80x94C1-3-alkyl, F, Cl, CH3, xe2x80x94CF2H or xe2x80x94CF3 in the meta-position, or para-CF3, or if R5 is a para-Cl or para-F, R4 represents meta-Cl or meta-F, or R4 and R5 together represent 3,4-OCHxe2x95x90CH2xe2x80x94.
1-phenyl-3-dimethylaminopropane compounds of formula I are particularly preferred in which the R2 and R3 radicals have different meanings, in the form of their diastereoisomers of configuration Ia 
The present invention also relates to a method of preparing 1-phenyl-3-dimethylaminopropane compounds of formula I, in which the variable X represents OH, which is characterized in that a xcex2-dimethylaminoketone of formula II 
is reacted with an organometallic compound of formula III 
in which Z represents MgCl, MgBr, MgI or Li, to form a compound of formula I in which X represents OH.
The reaction of a xcex2-dimethylaminoketone with a Grignard reagent of formula III, in which Z represents MgCl, MgBr or MgI, or with an organolithium compound of formula III, can be carried out in an aliphatic ether, for example diethyl ether and/or tetrahydrofuran, at temperatures between xe2x88x9270xc2x0 C. and +60xc2x0 C. Organolithium compounds of formula II can be obtained by the replacement of halogen by lithium, for example, by reacting a compound of formula III, in which Z represents Cl, Br or I, with a solution of n-butyllithium in n-hexane. xcex2-dimethylaminoketones of formula II can be obtained from ketones of general formula IV 
by reaction with dimethylamine hydrochloride and formaldehyde in glacial acetic acid or in a C1-4-alkyl alcohol or by reaction with dimethylammonium ethylene chloride in acetonitrile using acetyl chloride as a catalyst (Synthesis 1973, 703).
Upon reaction of a xcex2-dimethylaminoketone of formula II, in which the variables R2 and R3 have different meanings, with an organometallic compound of formula III, 1-phenyl-3-dimethylaminopropane compounds of formula I are obtained having the relative configuration of formula Ia 
in which the X and the dimethylamino group are disposed threo in relation to each other. In contrast, if the reaction for the preparation of 1-phenyl-1-hydroxy-3-aminopropanes were carried out according to the method disclosed in DD 124 521, i.e. if xcex2-aminoketones corresponding to the formula V 
were reacted with an alkyl Grignard reagent R1MgHal, this would result in compounds with the relative configuration Ib 
in which the OH group and the dimethylamino radical are disposed erythro in relation to each other.
1-phenyl-3-dimethylaminopropane compounds of formula I, in which R4 and/or R5 constitute the OH group, can be prepared from the corresponding 1-(4(5)-methoxyphenyl)-3-dimethylaminopropanol compounds by selective ether cleavage with diisobutylaluminium hydride in an aromatic hydrocarbon, for example toluene, at a temperature between 60 and 130xc2x0 C. (Synthesis 1975, 617).
The present invention also relates to a method of preparing 1-phenyl-3-dimethylaminopropane compounds of formula I, in which X represents H, which is characterized in that a compound of formula I, in which X represents Cl, is reacted with zinc borohydride, zinc cyanoborohydride and/or tin cyanoborohydride.
The reaction is usually conducted in a solvent, for example diethyl ether and/or tetrahydrofuran, at a temperature between 0xc2x0 C. and 30xc2x0 C.
Compounds of formula I, in which X is H and Rand/or R5 constitute the OH group, can be prepared from the corresponding methoxyphenyl compounds by heating them for several hours with concentrated hydrobromic acid (Chem. Rev. 54, 615 (1954); J. Am. Chem. Soc. 74, 1316 (1952)).
The present invention further relates to a method of preparing 1-phenyl-3-dimethylaminopropane compounds of formula I, where X represents F, which is characterized in that a compound of formula I, in which X represents OH, is reacted with dimethylaminosulfur trifluoride in a solvent.
Suitable solvents include dichloromethane, 1,1,2-trichloroethane and/or toluene. The reaction is usually conducted at a temperature between xe2x88x9250xc2x0 C. and +30xc2x0 C. (Org. React. 35, 513 (1988)). If a compound of formula I with Xxe2x95x90OH is used in which R4 and/or R5 constitute OH groups, these OH groups must be protected before reaction with the fluorine compound, for example by reaction with benzoyl chloride.
The present invention also relates to a method of preparing 1-phenyl-3-dimethylaminopropane compounds of formula I, in which X represents Cl, which is characterized in that a compound of formula I, in which X represents OH, is reacted with thionyl chloride.
The reaction is usually conducted in the absence of solvent at a temperature between 0xc2x0 C. and 20xc2x0 C. Replacement of OH by Cl is effected while maintaining the configuration.
The present invention also relates to a method of preparing 1-phenyl-3-dimethylaminopropane compounds of formula I, in which X represents an OCOR6 group where R6 is a C1-3-alkyl, which is characterized in that a compound of formula I, in which X represents OH, is reacted with an acid chloride Clxe2x80x94COOR6.
The reaction is preferably conducted in a solvent, for example dichloromethane, toluene and/or tetrahydrofuran, at a temperature between xe2x88x9210xc2x0 C. and +30xc2x0 C.
1-phenyl-3-dimethylaminopropane compounds of formula I, in which R5 is H and R4 is a meta-phosphate group, meta-carbonate group, meta-carbamate group or meta-carboxylate group, can be obtained by the reaction of the corresponding 1-(3-hydroxyphenyl)-3-dimethylaminopropane compounds of formula I in the form of their alkali salts with an alkali salt of a dialkyl chlorophosphate, with an alkyl chloroformate, with an aryl isocyanate or with a carboxylic acid chloride. These reactions are usually conducted in a solvent, for example toluene, dichloromethane, diethyl ether and/or tetrahydrofuran, at temperatures between xe2x88x9215xc2x0 C. and +110xc2x0 C. (Drugs of the Future 16, 443 (1991); J. Med. Chem. 30, 2008 (1987) and 32, 2503 (1989); J. Org. Chem. 43, 4797 (1978); Tetrahedron Lett. 1977, 1571; J. Pharm. Sci. 57, 774 (1968)).
The compounds of formula I can be converted in a known manner into their salts with physiologically acceptable acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. Salt formation is preferably effected in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solution is suitable for the preparation of hydrochlorides.
1-phenyl-3-dimethylaminopropane compounds of formula I are toxicologically harmless, so that they are suitable as pharmaceutical active ingredients in drugs.
Accordingly, the present invention also relates to the use of a 1-phenyl-3-dimethylaminopropane compound of formula I as a pharmaceutical active ingredient. Compounds of formula I are preferably used for the treatment of pain.
In addition to at least one 1-phenyl-3-dimethylaminopropane compound of formula I, the analgesics according to the invention may contain carriers, fillers, solvents, diluents, colorants and/or binders. The selection of auxiliary substances and of the amounts of the same to be used depends on whether the drug is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally or locally, for example for infections of the skin, of the mucous membranes or of the eye. Preparations in the form of tablets, dragees, capsules, granules, drops, liquids and syrups are suitable for oral application. Solutions, suspensions, readily reconstitutable dry preparations, and sprays are suitable for parenteral, topical and inhalative applications. Compounds of formula I according to the invention in a deposit in dissolved form or in a patch, optionally with the addition of a skin penetration promoter, are suitable preparations for percutaneous application. Forms of preparations which can be administered orally or percutaneously may effect delayed release of the compounds of formula I according to the invention.
The amount of active ingredient to be administered to patients varies depending on the patient""s weight, on the manner of administration, the indication and the degree of severity of the illness. 50 to 500 mg/kg of at least one 1-phenyl-3-dimethylaminopropane compound of formula I are usually administered.